The present application is a continuation of application Ser. No. 13/274,172 filed on Oct. 14, 2011, now U.S. Pat. No. 8,242,315 which is a continuation of application Ser. No. 12/596,800, filed on May 28, 2010, now U.S. Pat. No. 8,071,818 which is a 371 National Phase Application of PCT/US2008/063082 filed on May 8, 2008 which claims the benefit of U.S. provisional patent application No. 60/928,327 filed on May 9, 2007; U.S. provisional patent application No. 60/928,429 filed on May 9, 2007 and U.S. provisional patent application No. 60/928,296 filed on May 9, 2007.
Propofol (2,6-diisopropylphenol) is an intravenous sedative/hypnotic agent used extensively for induction and maintenance of general anesthesia, sedation of critically ill patients and procedural sedation (e.g., endoscopy). See Langly, M. S. and Heel, R. C. Drugs, 1988, 35, 334-372. Propofol is only sparingly soluble in water and is currently marketed in a 10% soybean oil based lipid emulsion similar to formulations used for parenteral nutrition.
Propofol is a GABAA agonist that activates multiple GABAA receptor subtypes, which are ion channels that transport chlorine anions across cell membranes, in the central nervous system. Although propofol is achiral, racemic mixtures of a number of dialkyl phenols are known agonists of the GABAA receptor (James et al., J. Med. Chem. 23, 1350, 1980; Krasowski et al., J. Pharmacol. & Exp. Therapeutics 297, 338, 2001). James et al., report finding propofol to be superior in its overall profile to other analogues evaluated.
Propofol is preferred by many clinicians due to its excellent pharmacokinetic, pharmacodynamic, emergence and recovery profiles. However, undesired side-effects (e.g., respiratory depression, ICU syndrome, injection pain and hemodynamic effects) produced at or near the therapeutic dose greatly limit its utility in multiple clinical settings. Of particular concern are the hemodynamic effects. Administration of propofol, particularly in bolus form, often produces decreases in blood pressure without a compensatory increase in heart rate. A variety of clinical conditions are incompatible with the use of propofol because of undesired and potentially harmful hemodynamic consequences. Examples of such conditions include cardiovascular disease such as coronary artery disease, cardiomyopathy, ischemic heart disease, valvular heart disease, and congenital heart disease. Chronic hypertension, cerebrovascular disease, brain injury, and advanced age can make the use of propofol difficult or problematic because of its hemodynamic properties. Patients with acute blood loss, dehydration, or severe infection including those with hemorrhagic shock, hypovolemic shock, or septic shock may be exposed to excessive hazard were propofol employed. The hemodynamic properties of propofol may limit its use in patients receiving other medications or treatments such as spinal anesthesia, epidural anesthesia, or vasoactive medications.